HIV-related Lymphomas Research Articles

Plasmablastic lymphoma achieving sustained remission with antiretroviral therapy alone

Despite advances in the treatment of most human immunodeficiency virus (HIV)-related lymphomas, the outcomes for patients with HIV-related plasmablastic lymphoma (PBL) remain poor. While studies have shown an increased survival for patients with most kinds of HIV-related lymphomas since the introduction of highly active antiretroviral therapy (HAART), the impact of HAART on survival in patients with HIV-related PBL is unclear, mainly because the condition is rare and the number of published studies is small. Few case reports have shown regression of PBL after initiation of HAART, however, usually followed by recurrence of PBL or achieved with a need for chemotherapy. We report the first case of PBL in a 38-year-old man with newly diagnosed HIV who achieved sustained remission after the initiation of HAART alone and who remains in remission seven years after diagnosis, without a need for chemotherapy or radiation. We illustrate the importance of initiating HAART therapy under the supervision of infectious disease specialists as soon as the PBL is diagnosed until future studies provide clear evidence in the management of HIV-related PBL.

HIV-related lymphomas in adults served in the public health network: An observational study.

Individuals infected with human immunodeficiency virus (HIV) have higher morbidity and mortality due to cancer, which is the third most common cause of death in this group, despite the high effectiveness of antiretroviral therapy (ART). We describe the clinical and laboratory characteristics, initial staging and outcome of HIV-related lymphoma.We included 18 patients in the study, of whom 61.1% were male, mean age 41 years. Nine of the 18 patients (50%) had a diagnosis of HIV infection concurrent with the diagnosis of lymphoma.The most common histological types were diffuse non-Hodgkin B-cell lymphoma, 8 patients (44.4%); and Burkitt lymphoma, 5 (27.8%) cases. The Cotswold revision of the Ann Arbor staging classification in 14 patients (77.7%) was between III and IV. B Symptoms were present in 11 patients (61.1%), bulky mass was observed in 11 cases (61.1%) and had extra-nodal involvement in 8 patients (44.4%).Of the 18 cases analyzed, 8 followed on to second-line treatment, wherein the CODOX-M/IVAC scheme (cyclophosphamide, adriamycin, vincristine, methotrexate/ifosfamide, etoposide, and cytosine arabinoside) was used in 3 of the cases. The second most common scheme was etoposide, doxorubicin, vincristine and cyclophosphamide (EPOCH), used in 2 cases (25%), while in single cases (12.5% each) cyclophosphamide, doxorubicin, vincristine, etoposide, and prednisone (CHOEP), ifosfamide, etoposide, and carboplatin (ICE) and dexamethasone, cisplatin, and cytarabine (DHAP) were used.In this series, we observed very high mortality, equivalent to 44.4%, and a complete response in only 11.1%, much lower than that observed by other authors.We found that patients diagnosed with lymphoma associated with HIV had an advanced early clinical staging, and evolved with low response rates to chemotherapy.

59P - Nivolumab treatment in patients with relapsed/refractory HIV-related lymphomas

59P - Nivolumab treatment in patients with relapsed/refractory HIV-related lymphomas

Causes and Predictors of Early Mortality in HIV-Positive and HIV-Negative Patients with Diffuse Large B-Cell Lymphoma

INTRODUCTION:There is a lack of data on early mortality in aggressive lymphomas, particularly HIV-related lymphomas. Patients who present with advanced disease and poor performance status are at a higher risk of adverse outcomes and are not offered clinical trial enrollment. Factors that may contribute to early mortality have not been delineated. In this retrospective analysis, we sought to identify causes and predictors of early mortality, occurring within 180 days of index diagnosis, in patients with HIV-positive and negative DLBCL, at an academic medical center.METHODS:We reviewed an electronic database to identify patients with a diagnosis of HIV-related DLBCL, treated at our center between January 1, 2005 and December 31, 2017. We further identified patients with non-HIV positive DLBCL diagnosed from January 1, 2015 to December 31, 2017. Data on patient demographics, clinical outcomes and treatment was collected. We defined early mortality as those patients who died within 180 days of diagnosis.RESULTS:HIV-NEGATIVE DLBCL: There were 103 HIV-negative patients with DLBCL, with a mean age of 65 years. N=17 (16.5%) patients expired within 180 days of diagnosis. In univariate analysis, factors predicting increased risk of mortality included poor ECOG performance status (PS) 3-4, presence of B-symptoms and higher international prognostic index (IPI) scores (Table 1). In multivariate analysis, poor PS (HR 4.86, p<0.03) and B-symptoms (HR 5.9, p<0.02) remained significant predictors of early mortality. Age, cell of origin and Hepatitis B/C positivity were not found to be predictive. The leading cause of death in the first 180 days was sepsis, attributing for 53% of mortality (Figure 1). Other commonly identified causes included progressive disease (23%), tumor lysis and cardiac complications (12%).HIV-POSITIVE DLBCL: We identified 82 patients with HIV-positive DLBCL and divided patients into Cohort A (N=25) patients who expired within 180 days and Cohort B (N=57), patients who were alive beyond 180 days. 9 patients died within the first 30 days, 20 patients within 90 days and 25 patients within 180 days of index diagnosis. Both groups predominantly consisted of African-Americans with advanced stage DLBCL with a mean age of 53 and 48 years respectively (p=0.02). In univariate analysis, more patients in Cohort A had Stage 3-4 DLBCL (100% vs. 86%), poorer ECOG PS of 3-4 (52% vs. 7%), higher IPI scores (56% vs. 11%), lower CD4 counts (median of 70 cells/uL vs. 140 cells/uL) and higher LDH (544 U/L vs. 270 U/L). In multivariate analysis, we found that poor ECOG PS (HR 2.4, p<0.0001), higher LDH (HR 1, p<0.008) and older age (HR 1.07, p<0.023) were associated with an increased risk of mortality at 180 days. The leading causes of death within 180 days were progressive disease in 48%, and sepsis in 32% of patients.We wanted to examine whether the time period of diagnosis affected mortality from HIV-related DLBCL in patients. Group 1 patients were diagnosed from January 2005 to December 2010 (N=20) and Group 2 from January 2011 to December 2017 (N=29). We found that in Group 1, 50% of patients died from progressive disease and 15% of patients died from an acute event. Meanwhile, in Group 2, 38% of patients died from progressive disease, and 52% died from an acute event. Sepsis was the most common acute event in both groups.CONCLUSION:Preventing early mortality in aggressive lymphomas is crucial to improving overall survival. For patients with non-HIV related DLBCL, we found poor ECOG PS and presence of B-symptoms to be predictors of early mortality. In patients with HIV-positive DLBCL, poor ECOG PS, higher LDH and older age were contributing factors. The leading cause of death in both HIV-positive and HIV-negative patients (2011- 2017) was sepsis followed by progressive disease at 180 days after diagnosis.Although sepsis is a major factor contributing to early mortality and morbidity, it is preventable with prophylaxis against opportunistic infections. In order to decrease sepsis related mortality, we propose early initiation of antimicrobial therapy in patients at high risk based on independent clinical variables identified in this study. A prospective study preventing sepsis in high risk patients is warranted to decrease early mortality in patients with aggressive lymphoma. [Display omitted] DisclosuresJanakiram:Seattle Genetics: Membership on an entity's Board of Directors or advisory committees.

Evaluation of Immune Recovery Following Autologous Hematopoietic Cell Transplantation in HIV-Related Lymphoma: Results of the BMT CTN 0803/AMC 071 Trial

Evaluation of Immune Recovery Following Autologous Hematopoietic Cell Transplantation in HIV-Related Lymphoma: Results of the BMT CTN 0803/AMC 071 Trial

Infectious Complications and Mortality after Autologous Stem Cell Transplantation for Lymphomas: A Comparison Between HIV-Infected and HIV-Negative Patients

▪Introduction: Lymphomas continue to be a leading cause of death in HIV-positive patients (HIV+ pts) in the cART era. The aim of this study was to review our 15-year single institution experience in performing Autologous Stem Cell Transplantation (ASCT) for HIV-infected and non-HIV patients with high-risk or relapsed lymphomas, focusing on infectious complications.Patients and Methods: We retrospectively evaluated our cohort of 28 HIV+ pts who underwent an ASCT between 2000-2015, and compared it with a well-matched control group of 39 HIV-negative pts.Patient and ASCT characteristics are described in Table 1. All HIV+ pts were on cART. Chemomobilization was used in 60% of the HIV cohort and 84% of the controls. BEAM conditioning regimen was the most common. All transplants were performed in the same tertiary hospital JACIE-accredited SCT unit.The primary end points were first-year cumulative incidence (CI) of infection, total infectious episodes and infection-related mortality. For the analysis, we defined 3 different time frames: 1st Pre-engraftment; 2nd from engraftment to day +100 and 3rd from day +100 until 1 year after SCT. Events occurring during the first 2 periods were considered early infections as compared to late.Results:All patients received antiviral and anti-PJP prophylaxis, but a significantly higher proportion of HIV+ pts were given antibacterial and antifungal prophylaxis (2/3 vs 1/3 approximately, Table 1). G-CSF support was initiated in all HIV recipients and 66% of controls, and the median days of use was longer for the HIV group (7 vs 4 days, p= 0.04). Median time to neutrophil engraftment was similar in both groups (13 vs 11 days, p=0.55); 93% of HIV pts and all control pts reached ANC > 500c/uL by day +30.Infectious episodes (IE) are described in Table 2, divided by pathogen subtype and time frame. Globally, all infection subtypes were more common in the HIV-infected cohort at some point.The most significant findings from the analysis are as follows. CI of early global infections: HIV 75% vs non-HIV 25% (p= 0.04), Figure 1. Median number of global infectious events: HIV 65 vs non-HIV 39 (p= 0.002; OR 1.8 [1.2-2.8]). Bacteria: CI of pre-engraftment and early bacterial infections were not different among groups (42% vs 28%, p= 0.47), but the median number of bacterial episodes was clearly different: HIV 17 vs non-HIV 12 (p= 0.08; OR 2.16 [0.96-4.8]). Fungi: CI of early fungal infections: HIV 10.7% vs non-HIV 0% (p= 0.03); minor infections were not considered. Viruses: CI of early viral infections: HIV 46% vs non-HIV 15% (p= 0.004). Median nº of early viral IE: HIV 19 vs non-HIV 6 (p= 0.007; OR 4.16 [1.43-12]). CI of late viral infections: HIV 30% vs non-HIV 11.7% (p= 0.04). CMV reactivations were by far more common in the HIV cohort (p=0,01). HIV viral load bleeps were documented in 35% of the HIV patients (most commonly in the day +30 control) and one post-transplant virological failure was diagnosed, forcing HAART substitution.Of note, 1st year CI of infection-related mortality was 14% in the HIV group vs 0% in the non-HIV group (p= 0.01), Figure 2. Three HIV+ pts suffered early fulminant septic episodes (1 E. coli + Enterococcus, 1 Rothia mucilaginosa, 1 non-clarified - possible Stenotrophomonas maltophilia) and a 29-year old woman in CR after a 1st line for a stage IVsB Burkitt-like lymphoma died due to a severe influenza A pneumonia. Length of admission was also significantly longer for the HIV+ pts (median days 34 vs 28, p=0.041).Regarding long-term outcome, median follow up as of July 2016 is 82 months for the HIV+ group and 70 months for the control group: 57% and 61% of the pts in each cohort are still alive, respectively. One HIV-infected pt and 3 controls have been lost to follow-up. EFS: 1 year 71.4% vs 81.9% (ns); 5 years: 63.9% vs 66.5% (ns). Overall Survival: 1 year 75% vs 84% (ns); 5 years 66.3% vs 74.6% (ns).Conclusion: Autologous stem cell transplantation has been proven to be feasible and effective in HIV-related lymphomas, but in our experience and despite great advances in cART and virological control, HIV+ patients are at high risk of infection and this might influence post-ASCT short-term survival. It is mandatory to focus on prophylactic and supportive measures and to choose carefully the optimal timing for transplantation. [Display omitted] [Display omitted] [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Extracavitary primary effusion lymphoma associated with hemophagocytic lymphohistiocytosis.

Extracavitary primary effusion lymphoma associated with hemophagocytic lymphohistiocytosis.

Quantitative PCR for Plasma Epstein-Barr Virus Loads in Cancer Diagnostics.

Epstein-Barr virus (EBV) is the causative agent of infectious mononucleosis and is associated with posttransplant lymphoproliferative disease (PTLD), Hodgkin's lymphoma, Burkitt's lymphoma, nasopharyngeal carcinoma, and HIV-related lymphomas. It infects nearly all humans and then persists for the life of the host in a small proportion of benign B lymphocytes. EBV reactivation, usually in the setting of immunosuppression, is the main risk factor for development of EBV-associated malignancies. EBV reactivation can be detected in tissue specimens using EBV-encoded RNA (EBER) in situ hybridization (ISH), which is routinely used for diagnosis of PTLD and nasopharyngeal carcinoma. However, EBER ISH cannot be routinely used for screening asymptomatic or monitoring posttreatment outcome due to difficulty in obtaining tissue specimens for testing and the nonquantitative nature of the assay. Recent studies have shown that EBV genomic DNA can be detected in blood of patients with EBV-associated diseases, and that monitoring of EBV viral load in blood could be an effective method of distinguishing disease-associated EBV reactivation from incidental EBV present in benign B lymphocytes, and could be used for diagnostic screening and monitoring of EBV-associated diseases. In this chapter we discuss a protocol for quantitative plasma EBV DNA analysis.

Adult T-cell leukaemia/lymphoma in a patient with pulmonary tuberculosis and Norwegian scabies

Acute adult T-cell leukaemia (AATL) is a clinical subtype of adult T-cell leukaemia/lymphoma, a rare type of peripheral T cell lymphoma. It is associated with infection by the retrovirus Human T-Lymphotropic Virus Type-1 (HTLV-1), and is seen most commonly in HTLV-1 endemic areas. The tumour cells have polylobulated nuclei morphologically and are CD3+, CD4+ or CD8+, CD7-, express T-cell receptor , and are CD25+. The disease has an aggressive clinical course associated with marked immunosuppression caused by HTLV-1, and a poor prognosis. We report a rare case of a young male patient who presented with AATL complicated by multiple opportunistic infections including pulmonary tuberculosis and Norwegian scabies. He also had chronic hepatitis B. This constellation of illnesses has not previously been reported from South Africa in a population where another retrovirus, Human Immunodeficiency Virus (HIV), is a far more common occurrence, as are the HIV-related lymphomas.

Stromal immune infiltration in HIV-related diffuse large B-cell lymphoma is associated with HIV disease history and patient survival.

Understanding tumor microenvironment and its impact on prognosis of HIV-related lymphomas may provide insight into novel therapeutic strategies. We characterized the relationship between infiltrating immune cells with tumor characteristics, HIV disease history and survival in 80 patients with HIV-related diffuse large B-cell lymphoma (DLBCL) diagnosed in the era of combined antiretroviral therapy (1996-2007) at Kaiser Permanente California. Eighty patients with HIV-unrelated DLBCL were included for comparison. Data on patients' clinical history were obtained from Kaiser Permanente's electronic health records. The density of stromal CD4, CD8 and FOXP3 T cells and CD68 macrophages, as well as tumor molecular characteristics were examined using immunohistochemistry. The associations between stromal immune infiltration and patient's clinical history or tumor characteristics were examined using Kruskal-Wallis tests or Pearson's correlation coefficient. The effect of stromal immune infiltration on 2-year mortality was evaluated in multivariable logistic regression. Compared with HIV-unrelated DLBCL, patients with HIV-related DLBCL had significantly reduced stromal CD4 and FOXP3 T cells, but increased density of macrophages. Increased density of stromal macrophages was correlated with lower circulating CD4 cell count at DLBCL diagnosis. Tumor molecular characteristics, including BCL6, p53 and cMYC expression, but not Epstein-Barr virus infection status, were significantly correlated with stromal immune infiltration, particularly FOXP3 T cells. A higher density of infiltrating CD8 T cell was significantly associated with reduced mortality in patients with HIV-related DLBCL (odds ratio = 0.30 [0.09-0.97] for ≥25 vs. <10%). These data provide evidence for the prognostic significance of cytotoxic T cells in determining outcomes of HIV-related lymphoma.

Epstein-Barr Virus Viral Loads and Serum Free Light Chains Levels Are Diagnostic Markers of Lymphoma in HIV-Infected Patients

IntroductionEpstein-Barr virus (EBV) viral load and serum free light chains (sFLC) are easily measurable and are possible biomarkers for screening and prognosis in HIV-related lymphomas. EBV load and sFLC levels have been shown to be increased at the diagnosis of HIV-related lymphomas but there is a lack of data on their levels at complete response (CR). We aimed to determine the clinical relevance and the potential use of combining EBV load and sFLC measurements as tumor markers in patients with HIV-related lymphomas.MethodsRetrospective study of HIV-infected patients diagnosed with non-Hodgkin (NHL) and Hodgkin’s lymphoma (HL) treated in a single institution from 1998 to 2012. EBV loads were determined in plasma by means of a commercial real-time PCR technique (EBV PCR kit, Qiagen GmbH, Hilden, Germany). Levels of κ and λ sFLC were measured in serum using a standardized assay (FREELITE, The Binding Site, Birmingham, UK). sFLC were considered elevated when κ, λ, or the sum of κ and λ were above the upper normal limit. Clinical and biological data were collected from the clinical records.ResultsSixty-eight patients were studied (53 NHL and 15 HL). At diagnosis (N=47), levels of κ, λ, and sum of κ and λ sFLC were elevated in 87%, 70%, and 81% of patients, respectively. At CR (N=29), the percentage of patients with elevated κ, λ, and κ+λ was 79%, 45%, and 62%, respectively. EBV load was detectable in 60% of the patients at diagnosis (N=50) and in 7.4% at CR (N=27). Median levels of κ, λ, and κ+λ sFLC at diagnosis were higher than at CR (6.06 mg/dL vs 3.19 mg/dL, P=0.006; 3.94 mg/dL vs 2.21 mg/dL, P=0.021; 11.38 mg/dL vs 5.43 mg/dL, P=0.004; respectively). Median levels of EBV loads at diagnosis were also higher than at CR (121.5 copies/mL vs. 0 copies/mL, P<0.001). There were fewer patients with elevated λ and κ+λ levels and detectable EBV loads at CR than at diagnosis (P=0.028, P=0.071 and P<0.001); respectively).Detectable EBV loads were associated with elevated λ (P=0.023) and κ+λ levels (P=0.055). Among the cases with detectable EBV load, 76% had elevated λ levels and 86% had elevated κ+λ levels. Moreover, median levels of κ and of κ+λ were higher in patients with detectable EBV loads than in patients with undetectable EBV loads (7.56mg/dL vs. 3.23 mg/dL, P=0.012 and 12.91mg/dL vs. 5.48mg/dL, P=0.022; respectively).EBV load and levels of sFLC were compared between groups defined by the clinical-biological features. At diagnosis, more patients with AIDS criteria before lymphoma showed increased λ sFLC than patients without AIDS criteria before lymphoma and the median levels of λ were higher in the group of patients with previous AIDS criteria. EBV loads were higher in patients without AIDS criteria before lymphoma. Patients with detectable HIV loads showed higher levels of λ than patients with undetectable HIV loads. However, all the former differences only showed a trend without reaching statistical significance.At CR, median level of λ sFLC was higher in patients who presented Bulky disease at diagnosis than in patients without Bulky (P=0.077). The median levels of κ, λ and κ+λ at CR were higher in patients with detectable HIV loads at diagnosis than in those with undetectable loads (P=0.032, P=0.064 and P=0.045; respectively). All 4 patients with undetectable HIV loads had normal κ+λ levels at CR. Unlike, only 6 out of 21 patients with detectable HIV loads had normal κ+λ levels (P=0.017) at CR. Patients treated with combination antiretroviral therapy (cART) before lymphoma presented lower κ levels at CR than patients not previously treated with cART (P=0.081). Also, increased κ and λ levels at CR were more frequently found in patients not treated with cART before lymphoma than in those previously treated (κ= 93% vs. 64%, P=0.080 and λ= 60% vs. 29%, P=0.089).Neither elevated sFLC levels nor positive EBV loads at diagnosis had impact on overall survival, progression-free survival or disease-free survival.ConclusionsIn patients with HIV-related lymphomas detectable EBV loads were associated with higher sFLC levels. At lymphoma diagnosis both sFLC levels and EBV loads were higher than at CR pointing they may be used as lymphoma markers. The control of HIV-infection was related to lower sFLC levels both at diagnosis and at CR.This work was supported in part by grants EC11-041 and RD12/0036/0029 RTICC from “Instituto Carlos III” Spain and 2014 SGR225 (GRE) from Generalitat de Catalunya, and by Josep Carreras International Foundation. DisclosuresNo relevant conflicts of interest to declare.

No Increased Risk of Secondary Neoplasms in Patients Treated with Rituximab for Non-Hodgkin’s Lymphoma : A Meta-Analysis of 9 Trials

Background. Rituximab improved outcomes of all CD20+ non-Hodgkin lymphoma (NHL) subtypes. Rituximab induces a transient B-cell depletion and a dose-dependent T-cell inactivation (Stroopinsky et al., Cancer Immunol Immunother 2012) predisposing to T-cell dependent infections and to a potential impaired T-cell immunosurveillance. Secondary neoplasms (SN) is infrequent in trials including rituximab and the SN risk associated to rituximab across multiple trials has not been reported. We performed a systematic review of published trials comparing chemotherapy with or without rituximab to evaluate SN occurrence.Methods. Our primary endpoint was SN risk in patients with NHL treated with rituximab. We searched PubMed and Embase databases for randomised controlled trials on rituximab and lymphoma where rituximab constituted the only difference between treatment arms and where SN incidence or SN related death were reported. Authors were contacted for SN related rituximab exposure if not detailed. Chronic lymphocytic leukemia and HIV-related lymphomas were excluded due to increased risk of SN. Updated follow-up of eligible trials presented at annual meetings of the American Society of Clinical Oncology and American Society of Hematology were retrieved. Data were extracted independently by two authors. A random effects DerSimonian-Laird meta-analysis was performed to estimate the summary effect of rituximab on the hazard of SN. Statistical heterogeneity was tested using Woolf test.Results. We identified nine trials cumulating 4621 patients with 2312 exposed to rituximab and 2309 not exposed. These nine trials are known with the following names: PRIMA (1), GELA LNH98.5 (2), MINT (3), CORAL (4), IELSG-19 (5), EORTC20981 (6), OSHO#39 (7), SAKK 35/98 (8), RICOVER60 (9). Histology were diffuse large B cell (n=4), follicular (n=4) and marginal zone (n=1) lymphomas. Median age was 58.1 years. Sex distribution was available for seven trials with 1650 (47.6%) women and 1814 (52.4%) men. In all these trials but one (SAKK 35/98), rituximab was used associated with chemotherapy: CHOP, CHOEP, FCM, MCP, DHAP, ICE, or chlorambucil. At a median follow-up of 73 months [interquartile range: 72-84], a total of 334 SN was observed, including 169 SN in patients randomised to rituximab as compared to 165 SN in patients not randomised to rituximab (OR= 0.88; 95%CI: 0.66-1.19) (Figure 1). No evidence of significant heterogeneity was noticed across trials (p = 0.93). Notably, the proportion of females, histology subtypes, use of rituximab in first line, and use of rituximab over prolonged periods in maintenance did not influence SN risk (p = 0.94, p = 0.80, p = 0.87, p = 0.87 respectively). The SN risk was not increased in protocols administrating rituximab over periods of 8 months to 12 months (CORAL , OSHO#39) as opposed to periods of 24 months (PRIMA, EORTC20981) (p=0.86).Conclusions. This meta-analysis of nine trials randomising rituximab in NHL patients suggests no SN predisposition at a median follow-up of 6 years. SN risk associated with the combination of rituximab and new targeted therapies warrants prospective monitoring. [Display omitted] DisclosuresFleury:Lundbeck: Membership on an entity’s Board of Directors or advisory committees, Preceptorship Other. Pfreundschuh:Amgen: Membership on an entity’s Board of Directors or advisory committees, Research Funding; Boehringer Ingelheim: Membership on an entity’s Board of Directors or advisory committees; Celgene: Membership on an entity’s Board of Directors or advisory committees; Onyx: Membership on an entity’s Board of Directors or advisory committees; Pfizer: Membership on an entity’s Board of Directors or advisory committees; Roche: Membership on an entity’s Board of Directors or advisory committees, Research Funding; Spectrum: Research Funding. Salles:Roche: Honoraria, Research Funding. van Oers:Roche: Consultancy. Gisselbrecht:Roche: Research Funding. Zucca:Roche: Consultancy, Membership on an entity’s Board of Directors or advisory committees; Johnson and Johnson: Consultancy, Membership on an entity’s Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity’s Board of Directors or advisory committees. Herold:Roche Pharma AG/Germany: Honoraria, Research Funding. Ghielmini:Roche: Research Funding, Speakers Bureau.

Characteristics and Outcome of HIV Associated Classical Hodgkin’s Lymphoma Among 68 Patients Included in the French ANRS CO16 Lymphovir Cohort Study

Background: Human Immunodeficiency Virus (HIV) infection is associated with an increased risk of classical Hodgkin (cHL) and non-Hodgkin lymphomas (NHL). In the combined antiretroviral therapy (cART) era, while the incidence of NHL has declined, HL incidence has remained stable. In comparison to their HIV-negative counterpart, HIV-associated HLs present frequent high-risk characteristics: 1- mixed cellularity histological subtype, 2- advanced stage, presence of B symptoms and higher International Prognostic Score (IPS).Methods: The national prospective cohort of HIV-related lymphomas (ANRS CO16 Lymphovir cohort sponsored by Inserm-ANRS) enrolled adult patients in 40 centers since July 2008. Pathological materials were centralized and reviewed. Diagnoses were based on World Health Organization criteria. Patients have been followed every 6 months during 5 years. HIV HL patients were compared to a series of HIV-negative adult patients consecutively diagnosed with HL during the same period in Paris Saint-Louis hospital.Results: Among 159 HIV-infected patients, 68 (43%) were diagnosed with cHL. Mixed cellularity (MC) subtype was predominant (n=42), followed by nodular sclerosing (11). Fifteen cases could not be subclassified mainly because of small needle biopsies. Median age was 44 years (ranging from 20 to 65), male/female ratio was 5.8. Most patients (75%) had advanced clinical stage (III/IV). HIV infection had been diagnosed for a median of 13 years (maximum of 26 years) before the diagnosis of cHL. Median CD4 T-cell count was 380/μl (range 37-1742) and plasma HIV RNA was < 50 in 78% of the patients. All except one patient had been treated with cART prior to cHL diagnosis. They were all treated with cART after diagnosis. Front-line chemotherapy with standard anthracyclin based regimen (ABVD) was given to 64 out of 68 patients, BEACOPP in 4 patients. ABVD was followed by radiotherapy in limited stages. Five patients died from early disease progression (n=2), sepsis during chemotherapy (1) and after relapse (2).Two-year overall survival and Progression Free Survivals (PFS) were 94% [95%CI 88, 100] and 89% [82, 97], respectively. The only factor associated with PFS was age with a relative risk of 8.09 [0.97; 67.18] above 45 years (Table). IPS and CD4 count were not significantly associated with PFS. In comparison with HIV-negative patients, patients with HIV infection displayed higher risk features for all prognostic factors of HL (older age, male predominance, MC subtype, more advanced stages, lower lymphocytic counts). Treatment of HIV-negative patients was similar to HIV-positive patients: ABVD (79%), BEACOPP (21%), with addition of radiotherapy in limited stages. Overall, the outcomes of the HIV-infected patients did not differ significantly from those of HIV-negative patients (Figure).Conclusion : Although high risk features still predominate in HIV-HL, the prognostic of these patients has markedly improved in the recent cART era. We report 2-years OS and PFS of 94% and 89%, respectively, in patients mainly treated with cART and ABVD. The outcome of HL in HIV infected patients now resembles to those of non HIV infected patients.Table:Univariate analysis of Progression Free Survival in HIV associated Hodgkin Lymphoma (Cox model) (N=68)NProgression or Death, NRR95 % CIp-valueGender0.95F911M5960.94[0.11 ; 7.77]Age0.05<453811≥453068.09[0.97 ; 67.18]Ann-Arbor stage0.77I-II1611III2021.54[0.14; 17.00]IV3242.09[0.23; 18.72]Hemoglobin, g/dL0.23≥10.54431<10.52442.5[0.56 ; 11.16]Leucocytes, x109/L0.14<156661≥15214.94[0.59 ; 41.05]Lymphocytes, x109/L*0.49≥0.65351<0.61221.79[0.35 ; 9.21]Albumin, g/L**0.40>=401811<404262.50[0.30 ; 20.76]IPS **0.320-219113-74162.91[0.35 ; 24.20]CD4 cell count, x109/L ***0.52> 0.24541≤0.22131.64[0.37 ; 7.32] RRRelative Risk CIConfidency interval*: 3 missing values**: 8 missing values***: 2 missing valuesMedian follow-up:HIV(-) cHL: 37 months (IQR=37) Lymphovir33 months (IQR=34)2- year PFS:HIV(-) cHL: 0.86 CI95%=[ 0.82, 0.90 ] Lymphovir0.89 CI95%=[ 0.82, 0.97 ] [Display omitted] IQRInterquartile range CIConfidency interval DisclosuresBrice:Seattle Genetics, Inc.: Research Funding; Takeda Pharmaceuticals International Co.: Honoraria, Research Funding; Roche: Honoraria.

HIV-1 Tat induces DNMT over-expression through microRNA dysregulation in HIV-related non Hodgkin lymphomas.

BackgroundA close association between HIV infection and the development of cancer exists. Although the advent of highly active antiretroviral therapy has changed the epidemiology of AIDS-associated malignancies, a better understanding on how HIV can induce malignant transformation will help the development of novel therapeutic agents.MethodsHIV has been reported to induce the expression of DNMT1 in vitro, but still no information is available about the mechanisms regulating DNMT expression in HIV-related B-cell lymphomas.In this paper, we investigated the expression of DNMT family members (DNMT1, DNMT3a/b) in primary cases of aggressive B-cell lymphomas of HIV-positive subjects.ResultsOur results confirmed the activation of DNMT1 by HIV in vivo, and reported for the first time a marked up-regulation of DNMT3a and DNMT3b in HIV-positive aggressive B-cell lymphomas. DNMT up-regulation in HIV-positive tumors correlated with down-regulation of specific microRNAs, as the miR29 family, the miR148-152 cluster, known to regulate their expression. Literature reports the activation of DNMTs by the human polyomavirus BKV large T-antigen and adenovirus E1a, through the pRb/E2F pathway. We have previously demonstrated that the HIV Tat protein is able to bind to the pocket proteins and to inactivate their oncosuppressive properties, resulting in uncontrolled cell proliferation. Therefore, we focused on the role of Tat, due to its capability to be released from infected cells and to dysregulate uninfected ones, using an in vitro model in which Tat was ectopically expressed in B-cells.ConclusionsOur findings demonstrated that the ectopic expression of Tat was per se sufficient to determine DNMT up-regulation, based on microRNA down-regulation, and that this results in aberrant hypermethylation of target genes and microRNAs.These results point at a direct role for Tat in participating in uninfected B-cell lymphomagenesis, through dysregulation of the epigenetical control of gene expression.

Relevance of miR-21 in HIV and non-HIV-related lymphomas.

The critical role of microRNAs (miRNAs) in cell differentiation, homeostasis and cancer development has been extensively discussed in recent publications. The microRNAs with RISC enzyme complex allow it to find its complementary sequence, which is usually located in the 3'-untranslated region (UTR) of the target messenger RNA (mRNA). This is followed by inhibition of protein translation or promotion, resulting in degradation of the target gene. miR-21 has been mapped at chromosome 17q23.2, where it overlaps with the protein coding gene vacuole membrane protein 1 (VMP1), a human homologue of rat vacuole membrane protein. Recent evidence indicates that miR-21 plays a vital role in tumour cell proliferation, apoptosis and invasion. The inhibition of miR-21 may induce cell cycle arrest and increased chemosensitivity to anticancer agents, providing evidence that miR-21 functions as an oncogene in human cancer. Increased expression levels of miR-21 were observed in tumours arising from diverse tissue types. This also includes tumours of haematological origin, such as chronic lymphatic leukaemia, diffuse large B cell lymphomas (DLBCLs), acute myeloid leukaemia and Hodgkin lymphomas. Recently, it has been shown that high levels of B cell activation were induced by miR-21 in circulating B cells and are seen in HIV-infected individual. Notably, miR-21 is overexpressed in activated B cells, suggesting its assistance in maintaining B cell hyperactivation, which plays a pivotal role in HIV-infected cells. Therefore, miR-21 can be considered as a powerful biomarker in HIV-related lymphomas. The number of studies related to the role of miR-21 in HIV-related lymphomas is sparse; therefore, this mini review highlights the recent publications related to clinical impact and significance of miR-21, specifically in HIV- and non-HIV-related lymphomas.

Meta-analysis of the risk of secondary neoplasm in patients treated for non-Hodgkin lymphoma with rituximab.

e19541 Background: Rituximab has improved outcome of patients with CD20+ non-Hodgkin lymphoma (NHL). Rituximab induces a transient B-cell depletion and a dose-dependent T-cell inactivation predisposing to T-cell dependent infections. T-cells contribute to immunosurveillance, but rituximab has not been associated with secondary neoplasm (SN) in NHL. We performed a systematic review of published trials comparing chemotherapy with or without rituximab to evaluate SN risk. Methods: Primary endpoint was SN risk associated with rituximab in induction and/or maintenance for NHL treatment. We searched PubMed and Embase databases for randomized controlled trials on rituximab and lymphoma where treatment arms differed only from rituximab use and where SN incidence or related death were reported. Authors were asked for rituximab associated SN if not detailed. Chronic lymphocytic leukemia and HIV-related lymphomas were excluded due to increased SN risk. Updated follow-up presented at American Society of Clinical Onco...

HHV-8 Large T-cell Lymphoma

Non-Hodgkin lymphomas of B-cell origin are the most commonly encountered HIV-related lymphomas in adults and children. These lymphomas are often extranodal, involve the central nervous system or other sites, and have been found to behave in a more aggressive manner. We report an unusual case of a child with HHV-8-positive large T-cell lymphoma.

Characteristics of B-Cell Lymphomas in HIV/HCV-Coinfected Patients During the Combined Antiretroviral Therapy Era

Hepatitis C virus (HCV) infection is frequent among HIV-infected patients. We describe, the characteristics of 6 HIV/HCV-coinfected patients with B-cell non-Hodgkin lymphoma (NHL) included in a prospective cohort study of HIV-related lymphomas. Five of the 6 cases had features of marginal zone/lymphoplasmacytic NHL versus 1 of 33 HIV only-infected patients. Remarkably, anti-HCV treatment led to a hematological response in a patient with splenic marginal zone lymphoma. This supports the role of chronic antigenic stimulation by HCV on lymphomagenesis and further evaluation of HCV antiviral therapy in coinfected patients with NHL.

Neoplasms and infections as the main causes of death in patients in complete response to HIV‐related non‐Hodgkin lymphoma in the combination antiretroviral therapy era: a study out of a series of 146 patients

Neoplasms and infections as the main causes of death in patients in complete response to HIV‐related non‐Hodgkin lymphoma in the combination antiretroviral therapy era: a study out of a series of 146 patients

Lymphoid Proliferations Associated With Human Immunodeficiency Virus Infection

Individuals who are immune deficient are at an increased risk for developing lymphoproliferative lesions and lymphomas. Human immunodeficiency virus (HIV) infection is 1 of 4 clinical settings associated with immunodeficiency recognized by the World Health Organization (WHO) in which there is an increased incidence of lymphoma and other lymphoproliferative disorders. To describe the major categories of benign lymphoid proliferations, including progressive HIV-related lymphadenopathy, benign lymphoepithelial cystic lesions, and multicentric Castleman disease, as well as the different types of HIV-related lymphomas as defined by the WHO. The characteristic morphologic, immunophenotypic, and genetic features of the different entities will be discussed in addition to some of the pathogenetic mechanisms. The WHO classification of tumors of hematopoietic and lymphoid tissues (2001 and 2008), published literature from PubMed (National Library of Medicine), published textbooks, and primary material from the authors' current and previous institutions. HIV infection represents one of the clinical settings recognized by the WHO in which immunodeficiency-related lymphoproliferative disorders may arise. Although most lymphomas that arise in patients with HIV infection are diffuse, aggressive B-cell lesions, other lesions, which are "benign" lymphoid proliferations, may also be associated with significant clinical consequences. These lymphoproliferations, like many other immunodeficiency-associated lymphoproliferative disorders, are often difficult to classify. Studies of HIV-associated lymphoid proliferations will continue to increase our understanding of both the immune system and lymphomagenesis.